This invention relates to a process for preparing 1,2-dihydro-6-alkyl-2-oxo-5-(pyridinyl)-nicotinonitriles (I) essentially free of the corresponding amide impurity. Compounds of the type described are known in the art to be useful as cardiotonic agents.
Prior art processes for preparation of such compounds are often burdened by co-production of impurities that require unusual measures to achieve purity levels suitable for pharmaceutical applications. Purification of such compounds to meet pharmaceutical specifications requiring exceptionally high purity is difficult even in the laboratory and more so in manufacture of commercial quantities. Indeed, even prior successful purification procedures require numerous time and yield-consuming cycles of recrystallization.
Illustrative of the preparation of compounds (I) are those in U.S. Pat. Nos. 4,313,951, issued Feb. 2, 1982, 4,347,363, issued Aug. 31, 1982, and 4,469,871, issued Sep. 4, 1984. The present invention provides a method of purification of 1,2-dihydro-6-alkyl-2-oxo-5-(pyridinyl)-nicotinonitriles using significantly fewer cycles of recovery than are expected from processes in the art.
Derivatization is a well-known concept for converting impurities in a crude mixture to fractions that may be cleared by further treatment to separate these fractions from the product to be purified. While easily stated as a procedure, the derivatizing agent must be selected with great care. The agent should be essentially unreactive with the desired end product but quantitatively reactive with the impurity. The derivatized impurities must have sufficiently high solubility differentiation against the desired product to yield a purified product requiring few cycles of fractional removal.